MNHf81.26 l WORLD HEALTH ORGANIZATION l $Sic;, i 12 ORGANISATION MONDIALE DE LA SANT~? ENnISH ONLY . 4TH REVIEW OF PSYCHOACTIVE SUBSTANCES FOR I~TERNATIONALCONTROL h Geneva, 14-18 September 1981 Page 1. Introduction and Scope of Meeting .... 2 2. Review of AgonistIAntagonist Drugs ... 3 2.1 Chemistry, Pharmacology, Toxicology 3 2.2 Dependence Potential in Animals ............... 4 2.3 HumanPharmacology ..................... 5 2.4 Public Health and Social Problems .............. 6 i 3. ~otificationfrom the Government of Austria ............ 7 I I 4. Abuse of Mixtures of Pentazocine and Tripelenamine ........ 8 i 5. Control of Agonist/Antagonists Drugs under the 1961 Convention , , 8 d l 6. Scheduling of Agonist/Antagonists Drugs under the 1971 Convention 8 ! I' 7. Notification from the Government of Belgium 9 'I ............ !11 8. ~eviewof Exempt preparations ................... 9 i 1, 1, 8.1 WHO ~eviewProcedures 9 ! .................... l 8.2 Review of Notifications of Exemptions. ............ 10 *' 1 9. Dextropropoxyphene ........................ 14 :l < 10. Selection of ~opicsfor Future considerations ........... 14 4 11. Recommendations Relating to the WHO Process whereby Drugs are Considered fhr ~nternationalControl .............. 14 12. ~istofparticipants ....................... 16 13. List of ~ackgroundDocuments ................... 17 The issue of this document does not constitute Ce document ne constitue pas une publication. formal publication. It should not be reviewed, II ne doit faire I'objet d'aucun compte rendu ou ; abstracted or quoted without the agreement of r6surnh ni d'aucune citation sans I'autorisation de I , l1 the World Health Organization. Authors alone 170rganisationMondiale de la Sante. hes opinions ,I I l are responsible for views expressed in signed exprimees dans les articles signhs n'engagent I articles. que leurs auteurs. I t 1. Introduction and Scope of Meeting On behalf of the Director-General of WHO, Dr N. Sartorius, Director, Division of Mental Health welcomed the ~articipantsand emphasized the role and cooperation of representatives of other organizations including the United Nations Division of Narcotic Drugs (UNDND), International Narcotics Control Board (INCB), International Criminal Police Organization, International Council on Alcohol and Addiction and the WHO Collaborating Centres on Research and Training in Drug Dependence. The unique aspects of the current meeting were emphasized. Firstly, the active involvement of the concerned pharmaceutical companies who submitted their data to WHO to assist deliberations was initiated with the acknowledgement of the ~irector-General. Secondly, the consideration of a new class of analgesic drugs would involve the group in discussions of a primary problem in medicine - the development of new drugs for the relief of pain and suffering. Thirdly, the results of the deliberations of the group would relate and affect parallel activities of the . ., Division of Mental Health. These include (1) the development of guidelines in the context of the international treaties for the control of psychotropic and narcotic substances at the national level; (2) revision of the list of essential drugs for psychiatry and (3) the programme planning for the next decade, The objectives of the meeting were listed I to include (1) review of opiate agonistlantagonists analgesics, (2) review of various l notifications, (3) advice on future activities for this group and related groups during the: 1 next 3 to 5 years, and (4) consideration of the process itself whereby WHO conducts its l responsibilities under the 1961 Single convention on Narcotics and 1971 Convention on 1 Psychotropic Substances. I i < Dr Sankaran, Director, Division of Diagnostic, Therapeutic and Rehabilitative Technology, informed the Group of the importance of their deliberations in regard to the J 1 forthcoming revision of the list of essential drugs which includes analgesics and psychotropics and the production of technical information sheets on drugs designed to be used at the first level hospital. I The Group was then informed of the actions taken at the twenty-ninth session of the United Nations Commission on Narcotic Drugs with regards to recommendations formulated by the Review Group 22-24 September 1980 (MNHI80.28). The recornendations of WHO concerning preparations exempted by the ~eople's Republic of Bulgaria and the Government of Mexico i accord with article 3, paragraph 4 of the 1971 Convention were accepted by the Commission. The Commission also accepted the recommendation of WHO with regard to the request of the Federal Republic of Germany that preparations containing 150 mg or less of dextropropoxyphene be included in Schedule I11 of the Single Convention on Narcotic Drugs 1961. With regard to the notification of the Government of Austria made pursuant to article 3, paragraph 1 of the Single Convention on Narcotic Drugs, 1961, that pentazocin be placed in Schedule I, the Commission initially voted for temporary control. That yision on temporary control was later rescinded, with a provision that WHO act expediti In providing a recommendation. The Government of Spain had requested review of ~ommissio decision I (S-VI), in accord with article 3, paragraph 8 of the 1961 Convention. The Commission voted to maintain that decision and, at a later date, the Economic and Social Council confirmed the decision of the UN Commission on Narcotic Drugs to control dextropropoxyphene under Schedule I1 of the Single Convention. The Group was then informed of the project initiated in response to WHA resolution 33.27, paragraph 7 (3) on the development of guidelines in the context of the international treaties for the control of narcotic and psychotropic substances. WHO missions have visited Malaysia and Panama for a detailed review of national drug abuse policies. Further missions are planned to take place in Kuwait, Thailand, Morocco and Nigeria. These Guidelines are scheduled for presentation to the WHO Executive Board in January 1984. ~eviewof agonist/antagonist drugs !' 2.. '. ! ..-. The discussion of agonist/antagonist drugs centered upon the pharmacology, toxicology, . dapcndenceliability and particularly the possible public health and social consequences $ *t might attend the use of these agents. I"1' 'chemistry, Pharmacology, ~oxicology The chemical structures of the compounds under consideration are shown below: 1. t 1 <.*- I L, -- I ,. I! It .:: N-CH,~ $4CH1 I l 6- - .i-l!-cH3 OH CH, H0 OCH, r a- Figure L: a, Pentazocine; b, cyclazocine; c, nalbuphine; d, butorphanol; e, buprenorphine. 'r These compounds are not readily convertible into drugs in Schedule I and I1 of the Single Convention on Narcotic Drugs, 1961. The pharmacology and toxicology of the agonistlantagonist analgesics were discussed, As a class they have both analgesic and narcotic antagonist activity in both animals and *. humans. While there are some quantitative differences in this regard they are qualitativel similar. At equianalgesic doses they all depress respiration to the same degree as morph P Unlike morphine, however, larger doses of the agonist/antagonist analgesics do not cause greater respiratory depression and therefore apnea never or rarely occurs. with the exception of buprenorphine their respiratory depressant effects can be reversed by the pu antagonist naloxone, although it requires a higher dose than that needed with the narcotic The respiratory depressant effect of bu~renorphineis only partially reversed by naloxone, The cardiovascular effects of these drugs are mild and there are qualitative differences, Butorphanol, nalbuphine and buprenorphine lower blood pressure and produces bradycardia, Pentazocine and cyclazocine elevate blood pressure and produce tachycardia. In general, t acute and chronic toxicity of these compounds are unremarkable with the exception of hyperexcitability in the rat with butorphanol and hair loss in rats and dogs with buprenorphine. Effects on reproduction are minor and teratologic effects were not seen, The drugs are rapidly absorbed after intramuscular and subcutaneous administration a half life varying from about 2 hours with pentazocine to about 4 hours with buprenorph Pentazocine is the only drug of the group presently marketed as an oral formulation while buprenorphine is available as a sublingual medication. Pentazocine, cyclazocine and butorphanol are excreted mainly in the urine while nalbuphine and buprenorphine are excre mainly in the faeces. Drug metabolism does occur and they are all excreted mainly as conjugates. The side effects of this class of drugs are not, in the main, serious. The most frequently observed signs are sedation, dizziness, nausea and vomiting. Disturbing subjective effects at therapeutic doses are infrequent but occur most often with cyclazoci and pentazocine and least with nalbuphine. 2.2 Dependence Potential in Animals Animal data relevant to predicting the dependence potential of pentazocine, cyclazocin nalbuphine, butorphanol and buprenorphine were reviewed by the Group. Specifically, the drugs were considered in terms of their: (1) Morphine antagonist effects as revealed by the drugs ability to precipitate withdrawal signs in morphine dependent monkeys. (2) Physical dependence potential of the morphine type as revealed by the drugs ability to both suppress withdrawal signs in morphine dependent animals and produce physical dependence when repeatedly administered, (3) Reinforcing effects. (4) Ability to substitute for morphine as a discriminative